Cyclo-oxygenase-2 selective inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) are associated with increased risk of acute cardiovascular events. Only aspirin offers primary and secondary cardiovascular prophylaxis, but trials have not answered directly whether low-dose aspirin is cardioprotective with COX-2 inhibitors. A large inception cohort study showed that concomitant use of aspirin reduced risk of cardiovascular events when given with rofecoxib, celecoxib, sulindac, meloxicam, and indometacin but not when given with ibuprofen. In large trials assessing gastrointestinal safety, there were fewer gastrointestinal events in patients using both COX-2 inhibitors and aspirin than in those using non-selective NSAIDs and aspirin; significantly fewer uncomplicated upper gastrointestinal events took place in the MEDAL trial. Analysis of VIGOR and two capsule endoscopy studies showed significantly less distal gastrointestinal blood loss with COX-2 inhibitors than with non-selective NSAIDs. Endoscopy trials showed that low-dose aspirin does not diminish the gastrointestinal benefits of COX-2 inibitors over non-selective NSAIDs. In an elderly epidemiological cohort receiving aspirin, both celecoxib and rofecoxib reduced risk of admission for gastrointestinal events. Comparison of the cardiovascular and gastrointestinal risks is difficult: likelihood and severity of cardiovascular events differ between individuals, agents, and exposure. Mortality associated with gastrointestinal events is less frequent than with cardiovascular events, but asymptomatic ulcers can result in severe complications. Data support the conclusion that COX-2 inhibitors are preferable to non-selective NSAIDs in patients with chronic pain and cardiovascular risk needing low-dose aspirin, but relative risks and benefits should be assessed individually for each patient.

Genital herpes is the main cause of genital ulcers worldwide; the prevalence of herpes simplex virus (HSV) type 2 infections in the general population ranges from 10% to 60%. Most genital herpes is caused by HSV-2, although HSV-1 accounts for about half of new cases in developed countries. The risk of HIV acquisition is three times higher in people with HSV-2. Neonatal herpes is an uncommon but serious complication of genital herpes. Most genital HSV-2 infections are unrecognised and undiagnosed; infected individuals, even with mild symptoms, shed HSV, and can infect sexual partners. Since clinical diagnosis is neither sensitive nor specific, virological and type-specific serological tests should be used routinely. Oral antiviral drugs for HSV infections are safe and effective and can be used both to treat episodes and to prevent recurrences. Antiviral treatment of the infected partners and condom use reduce the risk of sexual transmission of HSV-2.

New evidence has suggested that people with asthma who are homozygous for arginine at aminoacid 16 of the beta2-adrenergic receptor (ADRB2) might not benefit from longacting beta2-agonist therapy. We, therefore, investigated whether ADRB2 polymorphisms affect response to longacting beta2-agonists in combination with inhaled corticosteroids.

In 1977, the US Food and Drug Administration revoked all licences for fibrinogen concentrate because of the risk for hepatitis infection and suspected lack of effectiveness. However, in Japan, fibrinogen concentrate was used routinely for treatment of obstetric bleeding until 1988. Even in 1997, academic texts by Japanese authorities in obstetrics still recommended that obstetricians use the product. An estimated 10 000 cases of hepatitis C infection are attributable to use of fibrinogen in Japan and are a result of authoritarianism that hindered effective policy changes. Scientists have a duty to refine repeatedly the quality of their evidence, and policymakers need to adjust existing policies continually to accord with the latest scientific evidence.

In this Review, we look at the relation between bereavement and physical and mental health. Although grief is not a disease and most people adjust without professional psychological intervention, bereavement is associated with excess risk of mortality, particularly in the early weeks and months after loss. It is related to decrements in physical health, indicated by presence of symptoms and illnesses, and use of medical services. Furthermore, bereaved individuals report diverse psychological reactions. For a few people, mental disorders or complications in the grieving process ensue. We summarise research on risk factors that increase vulnerability of some bereaved individuals. Diverse factors (circumstances of death, intrapersonal and interpersonal variables, ways of coping) are likely to co-determine excesses in ill-health. We also assess the effectiveness of psychological intervention programmes. Intervention should be targeted at high-risk people and those with complicated grief or bereavement-related depression and stress disorders.

This paper estimates the disease burden and loss of economic output associated with chronic diseases-mainly cardiovascular diseases, cancer, chronic respiratory diseases, and diabetes-in 23 selected countries which account for around 80% of the total burden of chronic disease mortality in developing countries. In these 23 selected low-income and middle-income countries, chronic diseases were responsible for 50% of the total disease burden in 2005. For 15 of the selected countries where death registration data are available, the estimated age-standardised death rates for chronic diseases in 2005 were 54% higher for men and 86% higher for women than those for men and women in high-income countries. If nothing is done to reduce the risk of chronic diseases, an estimated US$84 billion of economic production will be lost from heart disease, stroke, and diabetes alone in these 23 countries between 2006 and 2015. Achievement of a global goal for chronic disease prevention and control-an additional 2% yearly reduction in chronic disease death rates over the next 10 years-would avert 24 million deaths in these countries, and would save an estimated $8 billion, which is almost 10% of the projected loss in national income over the next 10 years.

Interventions to prevent morbidity and mortality from chronic diseases need to be cost effective and financially feasible in countries of low or middle income before recommendations for their scale-up can be made. We review the cost-effectiveness estimates on policy interventions (both population-based and personal) that are likely to lead to substantial reductions in chronic diseases--in particular, cardiovascular disease, diabetes, cancer, and chronic respiratory disease. We reviewed data from regions of low, middle, and high income, where available, as well as the evidence for making policy interventions where available effectiveness or cost-effectiveness data are lacking. The results confirm that the cost-effectiveness evidence for tobacco control measures, salt reduction, and the use of multidrug regimens for patients with high-risk cardiovascular disease strongly supports the feasibility of the scale-up of these interventions. Further assessment to determine the best national policies to achieve reductions in consumption of saturated and trans fat--chemically hydrogenated plant oils--could eventually lead to substantial reductions in cardiovascular disease. Finally, we review evidence for policy implementation in areas of strong causality or highly probable benefit--eg, changes in personal interventions for diabetes reduction, restructuring of health systems, and wider policy decisions.

In 2005, WHO set a global goal to reduce rates of death from chronic (non-communicable) disease by an additional 2% every year. To this end, we investigated how many deaths could potentially be averted over 10 years by implementation of selected population-based interventions, and calculated the financial costs of their implementation. We selected two interventions: to reduce salt intake in the population by 15% and to implement four key elements of the WHO Framework Convention on Tobacco Control (FCTC). We used methods from the WHO Comparative Risk Assessment project to estimate shifts in the distribution of risk factors associated with salt intake and tobacco use, and to model the effects on chronic disease mortality for 23 countries that account for 80% of chronic disease burden in the developing world. We showed that, over 10 years (2006-2015), 13.8 million deaths could be averted by implementation of these interventions, at a cost of less than US$0.40 per person per year in low-income and lower middle-income countries, and US$0.50-1.00 per person per year in upper middle-income countries (as of 2005). These two population-based intervention strategies could therefore substantially reduce mortality from chronic diseases, and make a major (and affordable) contribution towards achievement of the global goal to prevent and control chronic diseases.

Chronic (non-communicable) diseases--principally cardiovascular diseases, cancer, chronic respiratory diseases, and diabetes--are leading causes of death and disability but are surprisingly neglected elements of the global-health agenda. They are underappreciated as development issues and underestimated as diseases with profound economic effects. Achievement of the global goal for prevention and control of chronic diseases would avert 36 million deaths by 2015 and would have major economic benefits. The main challenge for achievement of the global goal is to show that it can be reached in a cost-effective manner with existing interventions. This series of papers in The Lancet provides evidence that this goal is not only possible but also realistic with a small set of interventions directed towards whole populations and individuals who are at high risk. The total yearly cost of the interventions in 23 low-income and middle-income countries is about US$5.8 billion (as of 2005). In this final paper in the Series we call for a serious and sustained worldwide effort to prevent and control chronic diseases in the context of a general strengthening of health systems. Urgent action is needed by WHO, the World Bank, regional banks and development agencies, foundations, national governments, civil society, non-governmental organisations, the private sector including the pharmaceutical industry, and academics. We have established the Chronic Disease Action Group to encourage, support, and monitor action on the implementation of evidence-based efforts to promote global, regional, and national action to prevent and control chronic diseases.

In 2005, a global goal of reducing chronic disease death rates by an additional 2% per year was established. Scaling up coverage of evidence-based interventions to prevent cardiovascular disease in high-risk individuals in low-income and middle-income countries could play a major part in reaching this goal. We aimed to estimate the number of deaths that could be averted and the financial cost of scaling up, above current coverage levels, a multidrug regimen for prevention of cardiovascular disease (a statin, aspirin, and two blood-pressure-lowering medicines) in 23 such countries. Identification of individuals was limited to those already accessing health services, and treatment eligibility was based on the presence of existing cardiovascular disease or absolute risk of cardiovascular disease by use of easily measurable risk factors. Over a 10-year period, scaling up this multidrug regimen could avert 17.9 million deaths from cardiovascular disease (95% uncertainty interval 7.4 million-25.7 million). 56% of deaths averted would be in those younger than 70 years, with more deaths averted in women than in men owing to larger absolute numbers of women at older ages. The 10-year financial cost would be US$47 billion ($33 billion-$61 billion) or an average yearly cost per head of $1.08 ($0.75-1.40), ranging from $0.43 to $0.90 across low-income countries and from $0.54 to $2.93 across middle-income countries. This package could effectively meet three-quarters of the proposed global goal with a moderate increase in health expenditure.

Since the discovery of the haemochromatosis gene (HFE; chromosome 6p21.3) associated with haemochromatosis in 1996, many studies about diverse aspects of this common genetic disorder have been done. Some patients present with cirrhosis and show high mortality, whereas many asymptomatic homozygotes for the C282Y mutation in the haemochromatosis gene identified in population screening studies, who have been followed up for many years, do not develop iron overload. Studies described the usefulness of transferrin saturation and serum ferritin tests, and the acceptability of genetic testing for haemochromatosis. Phlebotomy therapy improves hepatic fibrosis. Here, we summarise some new findings in haemochromatosis, a disorder first described in 1865.

Age, sex, and blood pressure could modify the associations of total cholesterol (and its main two fractions, HDL and LDL cholesterol) with vascular mortality. This meta-analysis combined prospective studies of vascular mortality that recorded both blood pressure and total cholesterol at baseline, to determine the joint relevance of these two risk factors.

In the UK, about one in 200 infants is stillborn, and rates of stillbirth have recently slightly increased. This recent rise might reflect increasing frequency of some important maternal risk factors for stillbirth, including nulliparity, advanced age, and obesity. Most stillbirths are related to placental dysfunction, which in many women is evident from the first half of pregnancy and is associated with fetal growth restriction. There is no effective screening test that has clearly shown a reduction in stillbirth rates in the general population. However, assessments of novel screening methods have generally failed to distinguish between effective identification of high-risk women and successful intervention for such women. Future research into stillbirth will probably focus on understanding the pathophysiology of impaired placentation to establish screening tests for stillbirth, and assessment of interventions to prevent stillbirth in women who screen positive.

Since the prevalence of obesity continues to increase, there is a demand for effective and safe anti-obesity agents that can produce and maintain weight loss and improve comorbidity. We did a meta-analysis of all published randomised controlled trials to assess the efficacy and safety of the newly approved anti-obesity agent rimonabant.

The four dengue viruses are transmitted in tropical countries that circle the globe. All can cause syndromes that are self-limited or severe. The common severe syndrome--dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS)--is characterised by sudden vascular permeability generated by cytokines released when T cells attack dengue-infected cells. Dengue 1 virus became prevalent in Hawaii where it was transmitted by Aedes albopictus, producing a classic virgin soil epidemic, with clinical disease seen largely in adults. In Cuba and Singapore, sequential dengue infections at long intervals produced unusually severe disease in adults. Evidence suggests that enhancing and cross-reactive neutralising antibodies regulate dengue epidemics and disease severity. Classic DHF/DSS arises during initial dengue infections in infants with low circulating amounts of maternal dengue antibodies, an observation that precludes an exclusive causal role for secondary T-cell responses. Here, I review and discuss data on clinical diagnosis and pathophysiology of vascular permeability and coagulopathy, parenteral treatment of DHF/DSS, and new laboratory tests.

Combined oral contraceptives are classified by the International Agency for Research on Cancer as a cause of cervical cancer. As the incidence of cervical cancer increases with age, the public-health implications of this association depend largely on the persistence of effects long after use of oral contraceptives has ceased. Information from 24 studies worldwide is pooled here to investigate the association between cervical carcinoma and pattern of oral contraceptive use.

Despite declines in prevalence during the past two decades, sudden infant death syndrome (SIDS) continues to be the leading cause of death for infants aged between 1 month and 1 year in developed countries. Behavioural risk factors identified in epidemiological studies include prone and side positions for infant sleep, smoke exposure, soft bedding and sleep surfaces, and overheating. Evidence also suggests that pacifier use at sleep time and room sharing without bed sharing are associated with decreased risk of SIDS. Although the cause of SIDS is unknown, immature cardiorespiratory autonomic control and failure of arousal responsiveness from sleep are important factors. Gene polymorphisms relating to serotonin transport and autonomic nervous system development might make affected infants more vulnerable to SIDS. Campaigns for risk reduction have helped to reduce SIDS incidence by 50-90%. However, to reduce the incidence even further, greater strides must be made in reducing prenatal smoke exposure and implementing other recommended infant care practices. Continued research is needed to identify the pathophysiological basis of SIDS.

In the 1960s, total hip replacement revolutionised management of elderly patients crippled with arthritis, with very good long-term results. Today, young patients present for hip-replacement surgery hoping to restore their quality of life, which typically includes physically demanding activities. Advances in bioengineering technology have driven development of hip prostheses. Both cemented and uncemented hips can provide durable fixation. Better materials and design have allowed use of large-bore bearings, which provide an increased range of motion with enhanced stability and very low wear. Minimally invasive surgery limits soft-tissue damage and facilitates accelerated discharge and rehabilitation. Short-term objectives must not compromise long-term performance. Computer-assisted surgery will contribute to reproducible and accurate placement of implants. Universal economic constraints in healthcare services dictate that further developments in total hip replacement will be governed by their cost-effectiveness.

Velocardiofacial syndrome, DiGeorge syndrome, and some other clinical syndromes have in common a high frequency of hemizygous deletions of chromosome 22q11.2. This deletion syndrome is very common, affecting nearly one in 3000 children. Here, we focus on recent advances in cardiac assessment, speech, immunology, and pathophysiology of velocardiofacial syndrome. The complex medical care of patients needs a multidisciplinary approach, and every patient has his own unique clinical features that need a tailored approach. Patients with chromosome 22q11.2 deletion syndrome might have high level of functioning, but most often need interventions to improve the function of many organ systems.

The time is right to shift the focus of the global maternal health community to the challenges of effective implementation of services within districts. 20 years after the launch of the Safe Motherhood Initiative, the community has reached a broad consensus about priority interventions, incorporated these interventions into national policy documents, and organised globally in coalition with the newborn and child health communities. With changes in policy processes to emphasise country ownership, funding harmonisation, and results-based financing, the capacity of countries to implement services urgently needs to be strengthened. In this article, four global maternal health initiatives draw on their complementary experiences to identify a set of the central lessons on which to build a new, collaborative effort to implement equitable, sustainable maternal health services at scale. This implementation effort should focus on specific steps for strengthening the capacity of the district health system to convert inputs into functioning services that are accessible to and used by all segments of the population.